KR100969936B1 - Process For Preparing isoDecaprenol - Google Patents

Abstract

The present invention relates to a method for preparing decaprenol, and to solve the problems of the conventional decaprenol synthesis process using a coupling reaction and desulfonation reaction of a solaresyl bromide with a compound represented by the following formula (2): It is possible to manufacture decaprenol in an industrially safe and high yield. The prepared decaprenol may be used as a raw material of the antioxidant coenzyme qtene.

Decaprenol, coenzyme qtene, coupling reaction, desulfonation reaction, solanesil bromide, solanesol

Description

Process for Preparing (iso) Decaprenol}

The present invention relates to a novel process for the preparation of decaprenol using coupling and desulfonation reactions of solanesyl bromide with a compound of formula (2).

There are four known methods for synthesizing (iso) decaprenol.

Conventional synthesis process -1 [Refs. Helv., Chim., Acta. 2616-2621 (1959)]

The process -1 has a problem of process stability because it uses the explosive H ₂ .

Conventional Synthesis Process -2 [Ref.Shinsei Chemical Co., 9: 549 ~ 551 (2000)]

Since the process-2 uses human harmful substances such as mercury, the residue should be completely removed after the reaction is completed. In addition, it is a process that is important to note the process is not easy to commercial applications.

Conventional Synthesis Process -3 [Ref.Trav.Pays-Bas, 113: 153 ~ 161 (1994)]

In step -3, a strong metallic base such as NaH or Bu ₂ AlH and a reducing agent may generate hydrogen by moisture, and there is a risk of explosion.

Conventional Synthesis Process-4 [Reference US 2002/0156302 A1]

The process -4 has a disadvantage in that it is difficult to apply industrially because the Grignard Reaction reacts at a low temperature, and the operation process is complicated and the operating cost is large.

Therefore, the conventional synthesis process uses explosive substances or metal reagents, so the process stability is not suitable, and it is not suitable for industrial methods. Also, since toxic substances such as sulfur and mercury are harmful to the human body, such substances do not remain in the final product. There is a problem to avoid. In addition, the conventional synthesis process using the Grignard reaction is difficult to apply industrially, the process steps are too complex, there is a fundamental limitation that the operating cost is consumed in industrial applications, yield and purity are lowered.

Therefore, various attempts have been made to develop an economical industrial synthesis method that overcomes the problems listed above with the conventional method for preparing (iso) decaprenol. And a new method for producing dicaprenol using a desulfonation reaction, the following invention was completed.

A novel method for producing (iso) decaprenol on an industrial scale that avoids Grignard reaction conditions using magnesium, which is constrained by industrial processes, and minimizes process steps without the use of harmful compounds in the human body. To develop a manufacturing method.

The present inventors have diligently studied the conventional synthetic methods, and have discovered a new production method capable of preparing decaprenol by using a coupling reaction and a desulfonation reaction of a solenecil bromide with a compound represented by Formula 2 below.

The present invention does not use the harmful compounds used in the conventional synthesis, and does not use Grignard reagent, which has a risk of explosion in the process, so that (iso) decaprenol can be produced safely and industrially in high yield. have.

1) Use and structure of (iso) decaprenol

(Iso) decaprenol, one of polyprenol-derived substances, is a major raw material of coenzyme Q10 along with p-quinones, and as an antioxidant due to its chain length and stereoisomerism It determines the efficacy of the famous coenzyme Q10. Its structure is as follows.

2) Structural analysis and purity measurement of the reagents used in the synthesis and the obtained product

Solanesol (Aldrich, 95.0%), Phosphorous tribromide (Aldrich, PBr ₃ , 99.0%), ( E ) -4-Chloro (bromo) -2-methyl-1-phenylsulfonyl-2-butene (for convenience Substance of Formula 1, purity 98.5-99.9%), sodium acetate (Aldrich, CH ₃ CO ₂ Na, purity 99.0%), sodium benzoate (Aldrich, C ₆ H ₅ CO ₂ Na, purity 99.0%) methanol ( Daejeong Chemical, CH ₃ OH, Purity 99.0%), Tetrahydrofuran (Daejeong Chemical, THF, Purity 99.0%), Dichloromethane (Daejeong Chemical, CH ₂ Cl ₂ , Purity 99.0%), Potassium- t -butoxide (TCI , KO t Bu, purity 97.0%), palladium (diphenylphosphinoethane) dichloride (TCI, Pd (dppe) Cl ₂ ), lithium triethylborohydride (1M THF solution), potassium carbonate , K ₂ CO ₃ , purity 99.0%), t-butyllithium (Aldrich, 1M solution), ionic liquid (Kyrogen, 1-butyl-3-methyl-imidazolium tetrafluoroborate, purity 98.0% ) Etc.

2) Method of manufacturing decaprenol

2-1) Preparation of Solanesyl Bromide

A reflux condenser, a dropping device, and a magnetic stirrer are installed in a four-necked round bottom flask, and the raw material, Solanesol, is added as much as the calculated amount, and a dropping device is used to add phosphorus tribromide (PBr ₃ , 0.35 molar equivalent to Solanesol) by 1 ~. Add slowly over 2 hours. Thereafter, the temperature inside the reactor is raised to continue the reaction at reflux conditions. After the reaction was completed, an ice bath was installed in the reactor to cool the reactor, and then cold water (10 times volume ratio of PBr ₃ ) was added thereto, stirred for 0.5 to 1 hour, and then layer separation was performed. The separated product layer is washed twice with saturated aqueous NaCl solution (0.3 times volume ratio of cold water) and dried to obtain solaresyl bromide (hereinafter referred to as Sol-Br).

2-2) Preparation of Compound of Formula 2

A reflux condenser, a dropping device, and a magnetic stirrer were installed in a four-necked round bottom flask, and sodium carboxylate, a catalyst, and a solvent were added as calculated amount, and the temperature was raised to 90 ° C., followed by heating and stirring for 0.5 to 1 hour (E) The reaction is continued after the slow addition of -4-chloro (bromo) -2-methyl-1-phenylsulfoyl-2-butene (hereinafter referred to as compound of formula 1) by calculation amount under a stream of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Cold water (5 times the volume ratio of compound 1) and organic solvent (dichloromethane, ethyl acetate, chloroform, dichloroethane, etc. Volume ratio), and the mixture was stirred for 0.5 hours and then separated. Again, the cold water layer was extracted three times with an organic solvent, and all the organic layers were collected and washed twice with saturated aqueous NaCl solution. Thereafter, the organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a compound of Formula 2.

3) Preparation of (iso) decaprenol

3-1) Coupling Reaction of Solanesyl Bromide with Compound of Formula 2

After dissolving the compound of Formula 2 and Sol-Br in a solvent (5 vol. Ratio of Sol-Br) in a 4 neck round bottom flask, t-BuOK calculated at -20 ° C was dissolved in the solvent and added slowly over 1 to 2 hours. do.

This is stirred for 5-10 hours. After completion of the reaction, the solvent was distilled off, leaving only about 1/10 of the solvent, and saturated aqueous NH ₄ Cl solution was added, extracted with organic solvent (diethyl ether, dichloromethane, dichloroethane, ethyl acetate, etc.), and then magnesium sulfate (MgSO ₄ ). After drying, the organic solvent is distilled off to obtain a compound of formula 3.

3-2) Desulfonation of Compound of Formula 3

After dissolving the compound of formula 3 in a solvent (5 vol. Ratio of the compound of formula 3) in a four-necked round bottom flask, palladium (diphenylphosphinoethane) dichloride (Pd (dppe) Cl ₂ ) and 1M lithium tree at 0 ° C. Ethylborohydride (LiEt ₃ BH) is added sequentially. After the reaction was completed by stirring the reaction at 0 ° C. for 1 to 3 hours, when the reaction was completed, the solvent was distilled off while leaving only about 1/10 of the solvent, and a saturated NH ₄ Cl aqueous solution was added thereto, followed by an organic solvent (diethyl ether, After extraction with dichloromethane, dichloroethane, ethyl acetate, etc.) and drying with magnesium sulfate (MgSO ₄ ), the organic solvent is distilled off to obtain a desulfonated product.

3-3) Hydrolysis of Desulfonated Products

In a four-neck round bottom flask, the desulfonated product is dissolved in methanol (10 vol. Ratio of the desulfonated product), and potassium carbonate (K ₂ CO ₃ ) is sequentially added at room temperature. After stirring for 1 to 2 hours at room temperature, methanol was distilled off, and saturated NaHCO ₃ aqueous solution and an organic solvent (dichloromethane, dichloroethane, diethyl ether, ethyl acetate, etc.) were added, and the mixture was stirred for 0.5 hour and then separated. The separated organic solvent layer is dried over magnesium sulfate (MgSO ₄ ), and then the organic solvent is distilled off to obtain (iso) decaprenol, the final product.

3-4) Analysis method and result of prepared (iso) decaprenol

¹ H-NMR of the prepared (iso) decaprenol was measured using 400 MHz FT-NMR. Chemical shifts (δ) are expressed in parts per million (ppm) relative to the solvent used. Purity measurement was performed under the conditions of HPLC (column YMC-Pack ODS-AQ or equivalent, 210 nm, 1.0 ml / min, oven temperature 30 ° C.) using MeCN: H ₂ = 1: 1 as mobile phase and% of area. Represented by. And confirmation data was attached to each Example.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.90-5.98 (m, 1H, CH), 5.10-5.22 (m, 10H, CH), 2.06-2.11 (m, 20H, CH 2), 1.98-2.02 (t, 20H, allyl CH 2), 1.51-1.62 (m, 30H, CH 3) ppm. Purity is 96.5 area% on HPLC.

Synthesis Example 1 Preparation of Solanesyl Bromide

A reflux condenser, a dropping device, and a magnetic stirrer are installed in a 250 ml four-necked round bottom flask, and 63.1 g (0.1 mol) of solanesol (or solenesol) as a raw material is added thereto. 9.2 g (0.34 mole) of phosphorus tribromide (phosphorous tribromide; PBr ₃ ) is slowly added to the reactor over an hour by dropping apparatus. Thereafter, the temperature inside the reactor is raised to continue the reaction at reflux conditions. After the reaction was completed, an ice bath was installed in the reactor to cool the reactor, and then 100 ml of cold water was added thereto, stirred for 0.5 to 1 hour, and then the layers were separated. The separated product layer is dried to give Solanesyl bromide.

¹ H NMR (400 MHz, CDCl ₃ ) δ5.53-5.57 (t, 1H, CH), 5.09-5.15 (t, 9H, CH), 2.02-2.14 (t, 18H, CH2), 1.98-2.02 (t , 18H, allyl CH 2), 1.34 (s, 27H, CH 3) ppm.

Synthesis Example 2 Preparation of Compound of Formula 2 with Different Protection Group

A) Preparation of the compound of Formula 2-1 wherein R = methyl using sodium carboxylate

A reflux condenser, a dropping device, and a magnetic stirrer were installed in a 250 ml four-necked round bottom flask, and 14.8 g (0.18 mol) of sodium acetate (NaOAc) as a raw material and 3.99 g (0.015 g of tetrabutylammonium bromide (TBA-Br) as a catalyst Mole), 200 ml of THF was added and heated up to reflux, followed by heating and stirring for 0.5 to 1 hour, followed by ( E ) -4-chloro-2-methyl-1-phenylsulfonyl-2-butene under nitrogen stream. 36.6 g (0.15 mole) of the compound of Formula 1 in Formula 1 is slowly added and the reaction is continued. After 15 hours, the reaction was terminated. After cooling to room temperature, the THF was removed under reduced pressure, 160 ml of cold water and 200 ml of dichloromethane were added thereto, stirred for 0.5 hour, and the layers were separated. The cold water layer was extracted three times with dichloromethane and all organic layers were collected and washed twice with saturated aqueous NaCl solution. Thereafter, the organic layer was dried over magnesium sulfate (MgSO ₄ ), and then concentrated under reduced pressure to obtain 34.9 g (yield 87%) of the compound of formula 2 wherein R = methyl.

B) Preparation of the compound of Formula 2-2 wherein R = phenyl using sodium carboxylate

A 250 ml four-necked round bottom flask was equipped with a reflux condenser, a dropping device and a magnetic stirrer, and 25.9 g (0.18 mol) of sodium benzoate (NaOBn) as a raw material and 3.99 g (TBA-Br) as a catalyst. 0.015 mole), 200 ml of THF is added, heated to reflux, heated and stirred for 0.5-1 hour, and then slowly added 36.6 g (0.15 mole) of the compound of formula (X = Cl) under nitrogen stream to react. To last. After 15 hours, the reaction was terminated. After cooling to room temperature, the THF was removed under reduced pressure, 160 ml of cold water and 200 ml of dichloromethane were added thereto, stirred for 0.5 hour, and the layers were separated. The cold water layer was extracted three times with dichloromethane and all organic layers were collected and washed twice with saturated aqueous NaCl solution. Thereafter, the organic layer was dried over magnesium sulfate (MgSO ₄ ), and then concentrated under reduced pressure to obtain 42.1 g (yield 85%) of the compound of formula 2 wherein R = phenyl.

C) Preparation of a compound of Formula 2-1 wherein R = methyl using an ionic liquid

A reflux condenser, a dropping device, and a magnetic stirrer were installed in a 500 ml four-necked round bottom flask, and 14.8 g (0.18 mole) of sodium acetate (NaOAc) and an ionic liquid (1-butyl-3-methyl-imidazolium) were used. After adding 200 g (0.75 mol) of tetrafluoroborate, hereinafter referred to as BMITB, the temperature was raised to 90 ° C., and the mixture was heated and stirred for 0.5 to 1 hour, and then 36.6 g (0.15 mol) of Chemical Formula 1 (Cl) was added under nitrogen stream. Add slowly and continue the reaction. After 5 hours, the reaction was terminated. After cooling to room temperature, 500 ml of cold water and 500 ml of dichloromethane were added, the mixture was stirred for 0.5 hours, and the layers were separated. The dichloromethane layer was separated twice with cold water to remove the residual ionic liquid, and the organic layers were collected and washed with a saturated NaCl aqueous solution. Thereafter, the organic layer was dried over magnesium sulfate (MgSO ₄ ), and then concentrated under reduced pressure to obtain 32.15 g (yield 80%) of the compound of formula 2 wherein R = methyl.

D) Preparation of a Compound of Formula 2-2 wherein R = phenyl Using an Ionic Liquid

A reflux condenser, a dropping device, and a magnetic stirrer were installed in a 500 ml four-necked round bottom flask, and 25.9 g (0.18 mole) of sodium benzoate (NaOBz) and 200 g (0.75 mole) of BMITB were added until the temperature reached 90 ° C. 43.3 g (0.15) of ( E ) -4-bromo-2-methyl-1-phenylsulfonyl-2-butene (compound having X = Br in Chemical Formula 1) under a stream of nitrogen after heating and stirring under heating for 0.5 to 1 hour. Mole) is added slowly and the reaction is continued. After the reaction was completed after 3-4 hours, the mixture was cooled to room temperature, and 500 ml of cold water and 500 ml of dichloromethane (MC) were added thereto, stirred for 0.5 hour, and the layers were separated. The dichloromethane layer was separated twice with cold water to remove residual ionic liquid, and the organic layers were collected and washed with saturated NaCl aqueous solution. Thereafter, the organic layer was dried over magnesium sulfate (MgSO ₄ ), and then concentrated under reduced pressure to obtain 38.6 g (yield 77%) of the compound of formula 2 wherein R = phenyl.

Synthesis Example 3 Preparation of (Iso) Decaprenol

A-1) Coupling Reaction of Solanesyl Bromide with Compound of Formula 2-1 (R = methyl)

In a 500 ml four-necked round bottom flask, 18.7 g (0.07 mol) of Formula 2 (R = Me) and 51.3 g (0.074 mol) of solaresyl bromide obtained in Synthesis Examples 1 and 2, respectively, were dissolved in 250 ml of THF. 8.3 g (0.074 mol) of potassium t-butoxide (t-BuOK) is dissolved in 50 ml of THF at −20 ° C. and slowly added over 0.5 h. This is stirred for 5-10 hours. After completion of the reaction, THF was distilled off with only 20-30 ml remaining, saturated NH ₄ Cl aqueous solution was added, extracted with Et ₂ O, dried over MgSO ₄ , organic solvent was distilled off, and R = methyl compound 57.3 g (yield: 90%) is obtained.

A-2) Coupling Reaction of Solanesyl Bromide with Compound of Formula 2-1 (R = methyl)

In a 500 ml four-necked round bottom flask, 18.7 g (0.07 mol) of the compound of formula 2 (R = Me) obtained in Synthesis Examples 1 and 2 and 51.3 g (0.074 mol) of solanesil bromide were dissolved in 250 ml of THF. After addition, 74 ml (0.074 mol) of 1M n-butyllithium solution at −60 ° C. are slowly added over 0.5 hours. This is stirred for 5-10 hours. After completion of the reaction, THF was distilled off with only 20-30 ml remaining, saturated NH ₄ Cl aqueous solution was added, extracted with Et ₂ O, dried over MgSO ₄ , organic solvent was distilled off, and R = methyl compound 49.3 g (yield: 80%) is obtained.

A-3) Coupling Reaction of Solanesyl Bromide with Compound of Formula 2 (R = phenyl)

In a 500 ml four-necked round bottom flask, 23.1 g (0.07 mol) of the compound of formula 2 (R = phenyl) obtained in Synthesis Examples 1 and 2 and 51.3 g (0.074 mol) of solenesil bromide were dissolved in 250 ml of THF. Then, 8.3 g (0.074 mol) of potassium t-butoxide (t-BuOK) is dissolved in 50 ml of THF at −20 ° C. and slowly added over 0.5 hours. This is stirred for 5-10 hours. After completion of the reaction, THF was distilled off with only about 20-30 ml, saturated NH ₄ Cl aqueous solution was added, extracted with Et ₂ O, dried over MgSO ₄ , organic solvent was distilled off, and R = phenyl was used. Compound 56.0 g (yield: 85%) is obtained.

B-1) Desulfonation reaction of the compound of formula 3 wherein R = methyl

Dissolve 57.3 g (0.065 mol) of the compound of formula 3 (R = methyl) in 300 ml of THF in a 1000 ml four-necked round bottom flask, and then palladium diphenylphosphinoethane dichloride (Pd (dppe) Cl) at 0 ° C. ₂ ) 2.0 g (0.0033 mol) and 145 ml (0.137 mol) of 1M lithium triethylborohydride (LiEt ₃ BH) are added sequentially. After the reaction was completed by stirring the reaction at 0 ° C. for 1 to 3 hours, when the reaction was completed, the reaction mixture was distilled away with only 30 ml of THF, saturated NH ₄ Cl aqueous solution was added, extracted with Et ₂ O, followed by MgSO ₄ After drying, the organic solvent was distilled off to obtain 42.2 g (yield: 80%) of desulfonated product.

B-2) Desulfonation reaction of the compound of formula 3 wherein R = phenyl

In a 1000 ml four-necked round bottom flask, 61.2 g (0.065 mol) of Chemical Formula 3 (R = phenyl) was dissolved in 300 ml of THF, followed by 2.0 g (0.0033 mol) of Pd (dppe) Cl ₂ and 1M LiEt ₃ at 0 ° C. 145 ml (0.137 mol) of BH are added sequentially. After the reaction was completed by stirring the reaction at 0 ° C. for 1 to 3 hours, when the reaction was completed, the reaction mixture was distilled off with only 30 ml of THF, saturated NH ₄ Cl aqueous solution was added, extracted with Et ₂ O, and then MgSO ₄ After drying, the organic solvent was distilled off to obtain 47 g (yield: 90%) of desulfonated product.

C-1) Hydrolysis of Desulfonated Products

Dissolve 42.2 g (0.057 mol) of B) -1 desulfonated product of Synthesis Example 3) in 300 ml of methanol in a 500 ml four-necked round bottom flask, and then add 11.2 g of potassium carbonate (K ₂ CO ₃ ) at room temperature. 0.081 mol) are added sequentially. After stirring for 1-2 hours, methanol was distilled off, and 200 ml of saturated NaHCO ₃ aqueous solution and 500 ml of dichloromethane were added, and the mixture was stirred for 0.5 hours and then separated. After repeating this process two more times, the dichloromethane layer was dried with MgSO ₄ and dichloromethane was distilled off to obtain 37 g (yield: 93%) of (iso) decaprenol as a final product.

C-2) Hydrolysis of Desulfonated Products

45.7 g (0.057 mol) of b) -2 desulfonated product of Synthesis Example 3) was dissolved in 300 ml of methanol in a 500 ml four-necked round bottom flask, and then 11.2 g (0.081 mol) of K ₂ CO ₃ was sequentially added at room temperature. Is added. After stirring for 1-2 hours, methanol was distilled off, and 200 ml of saturated NaHCO ₃ aqueous solution and 500 ml of dichloromethane were added, and the mixture was stirred for 0.5 hours and then separated. After repeating this process two more times, the dichloromethane layer was dried with MgSO ₄ and dichloromethane was distilled off to obtain 35.8 g (yield) decaprenol (yield: 90%).

Various problems with the conventional synthesis process of (iso) decaprenol are solved by industrially safe and high yield by using the solaresyl bromide of the present invention and the coupling reaction and the desulfonation reaction of the formula (2). Can be.

Those skilled in the art will recognize that various changes and / or modifications may be made to aspects or aspects of the invention, and that such changes and / or modifications may be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalents falling within the spirit and scope of the invention.

Claims (5)

A method for preparing (iso) decaprenol comprising the following steps; Coupling a solaresyl bromide (Sol-Br) with a compound of Formula 2 in the presence of a solvent and a catalyst to obtain a compound of Formula 3, Dissolving the obtained compound of Formula 3 in a solvent, followed by addition of a desulfonation catalyst, followed by desulfonation reaction to obtain a desulfonation product, and Hydrolyzing this desulfonated product.

The process of claim 1 wherein the solvent used in the coupling reaction step is tetrahydrofuran and the catalyst is t-BuOK or n-butyllithium solution. The desulfonation reaction catalyst is a palladium (diphenylphosphinoethane) dichloride (Pd (dppe) Cl ₂ ) and lithium triethyl borohydride (LiEt ₃ BH), the solvent is tetrahydrofuran How to be. A compound of formula 2 prepared by reacting a compound of formula 1 with sodium carboxylate in the presence of a solvent and a catalyst as an intermediate of (iso) decaprenol of claim 1.

The intermediate of the (iso) decaprenol of claim 1, wherein the compound of formula (3) prepared by coupling reaction of solanyl bromide (Sol-Br) with the compound of formula (2) in the presence of a solvent and a catalyst.